phosphorylation of lkb1 at serine 428 by protein kinase c-ζ is

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1、NIHPublicAccessAuthorManuscriptCirculation.Authormanuscript;availableinPMC2010May3.NIH-PAAuthorManuscriptPublishedinfinaleditedformas:NIH-PAAuthorManuscriptNIH-PAAuthorManuscriptCirculation.2008February19;117(7):952±962.doi:10.1161/CIRCULATIONAHA.107.7444

2、90.PhosphorylationofLKB1atSerine428byProteinKinaseC-ζIsRequiredforMetformin-EnhancedActivationoftheAMP-ActivatedProteinKinaseinEndothelialCellsZhonglinXie,MD,PhD1,YunzhouDong,PhD1,RolandScholz,BS2,DietbertNeumann,PhD2,andMing-HuiZou,MD,PhD11DivisionofEndo

3、crinologyandDiabetes,DepartmentofMedicine,UniversityofOklahomaHealthSciencesCenter,OklahomaCity2InstituteofCellBiology,ETHZurich,Zurich,SwitzerlandAbstractBackground—Metformin,oneofmostcommonlyusedantidiabetesdrugs,isreportedtoexertitstherapeuticeffectsby

4、activatingAMP-activatedproteinkinase(AMPK);however,themechanismbywhichmetforminactivatesAMPKispoorlydefined.TheobjectiveofthepresentstudywastodeterminehowmetforminactivatesAMPKinendothelialcells.MethodsandResults—Exposureofhumanumbilicalveinendothelialcel

5、lsorbovineaorticendothelialcellstometforminsignificantlyincreasedAMPKactivityandthephosphorylationofbothAMPKatThr172andLKB1atSer428,anAMPKkinase,whichwasparalleledbyincreasedactivationofproteinkinaseC(PKC)-ζ,asevidencedbyincreasedactivity,phosphorylation(

6、Thr410/40ζ),andnucleartranslocationofPKC-ζ.Consistently,eitherpharmacologicalorgeneticinhibitionofPKC-ζablatedmetformin-enhancedphosphorylationofbothAMPK-Thr172andLKB1-Ser428,suggestingthatPKC-ζmightactasanupstreamkinaseforLKB1.Furthermore,adenoviralovere

7、xpressionofLKB1kinase-deadmutantsabolishedbutLKB1wild-typeoverexpressionenhancedtheeffectsofmetforminonAMPKinbovineaorticendothelialcells.Inaddition,metforminincreasedthephosphorylationandnuclearexportofLKB1intothecytosolsaswellastheassociationofAMPKwithL

8、KB1inbovineaorticendothelialcells.Similarly,overexpressionofLKB1wild-typebutnotLKB1S428Amutants(serinereplacedbyalanine)restoredtheeffectsofmetforminonAMPKinLKB1-deficientHeLa-S3cells,suggestingthatSer428phosphoryla